U.S. Pat. No. 4,225,608 (Uhl et al.) discloses phenoxyalkylamines of the formula: EQU AR--O--R
wherein:
Ar is phenyl optionally substituted with 1 or 2 substituents selected from the group: PA1 R is (1-R.sup.1 -2-pyrrolidyl)--CH.sub.2 --CHR.sup.2 --, (1-R.sup.1 -2-piperidyl)-CH.sub.2 --CHR.sup.2 -- or 1-R.sup.1 -3-Z-4-hexahydroazepinyl; PA1 R.sup.1 is H, alkyl or alkenyl each of up to 4 carbon atoms, cyclopropylmethyl or benzyl; PA1 R.sup.2 is H, alkyl of 1 to 4 carbon atoms or phenyl; and PA1 Z is alkyl of 1 to 4 carbon atoms with the proviso that Ar is p-fluorophenyl only if R is not 2-(1-methyl-2-piperidyl)-ethyl. The phenoxyalkylamine compounds have antidepressant activity. PA1 R.sup.2 is alkyl, alkenyl, hydroxyalkyl, cycloalkylalkyl, dimethylaminoalkyl, aralkyl, arylalkenyl, arylalkoxy, aryloxyalkyl, 2-halophenothiazinyl(10)-propyl, 10, 11-dihydro-5H-dibenzo (b,f)azepin-5-yl-propyl or 3-halo-10,11-dihydro-5H-dibenzo (b,f)azepinyl propyl. PA1 n is 0 to 3; PA1 provided that m and n are not both O; PA1 p is 0 to 3; PA1 X is O, S, SO, SO.sub.2, NR.sup.6, CR.sup.7 R.sup.8, ##STR4## or CHOH; R.sup.1, R.sup.3 and R.sup.7 independently are H, alkyl of 1 to 5 carbon atoms, halogen, NR.sup.10 R.sup.11, OH, CO.sub.2 H, carboalkoxy of 2 to 6 carbon atoms, CN, Ar.sup.1, alkoxy of 1 to 5 carbon atoms or alkylthio of 1 to 5 carbon atoms; PA1 R.sup.2, R.sup.4 and R.sup.8 independently are H, alkyl of 1 to 5 carbon atoms, carboalkoxy of 2 to 6 carbon atoms, CN, alkoxy of 1 to 5 carbon atoms or Ar.sup.1 ; PA1 provided that R.sup.1, R.sup.2, R.sup.3 and R.sup.4 are not alkoxy of 1 to 5 carbon atoms, alkylthio of 1 to 5 carbon atoms, NR.sup.1 OR.sup.11 or OH when X is O, S, SO, SO.sub.2 or NR.sup.6 ; PA1 R.sup.5 is H, alkyl, halogen, OH or alkenyl; PA1 R.sup.6 is H, alkyl of 1 to 5 carbon atoms or Ar.sup.1 ; PA1 Ar and Ar.sup.1 independently are naphthyl, pyridyl, pyrimidyl, indolyl, quinolinyl, isoquinolinyl, or phenyl optionally substituted with alkyl of 1 to 3 carbon atoms, alkoxy of 1 to 3 carbon atoms, haloalkyl of 1 to 3 carbon atoms and 1 to 7 halogen atoms, SH, S(O).sub.t alkyl of 1 to 3 carbon atoms, where t is 1, 2 or 3, dialkylamino of 2 to 6 carbon atoms, halogen, OH, alkylamino of 1 to 3 carbon atoms, NH.sub.2, CN, NO.sub.2, SO.sub.3 H, tetrazole, CO.sub.2 H, carboalkoxy of 2 to 6 carbon atoms, CONH.sub.2, SO.sub.2 NH.sub.2, COR.sup.9, CONR.sup.12 R.sup.13, SO.sub.2 NR.sup.12 R.sup.13, Ar.sup.2, OAr.sup.2 or SAr.sup.2 ; PA1 Ar.sup.2 is naphthyl or phenyl optionally substituted with alkyl of 1 to 3 carbon atoms, haloalkyl of 1 to 3 carbon atoms and 1 to 7 halogen atoms, alkoxy of 1 to 3 carbon atoms, halogen or alkylthio of 1 to 3 carbon atoms; PA1 R.sup.9, R.sup.10, R.sup.11, R.sup.12 and R.sup.13 independently are H, alkyl of 1 to 5 carbon atoms or phenyl or R.sup.10 and R.sup.11 taken together are an alkylene chain of 3 to 6 carbon atoms or R.sup.12 and R.sup.13 taken together are an alkylene chain of 3 to 6 carbon atoms; and PA1 a or b is a double bond or a single bond, provided that both are not double bonds. PA1 X is ##STR5## CHOH or O; and/or m is 0; and/or PA1 n and p are 1; and/or PA1 R.sup.3 -R.sup.5 are H; and/or PA1 Ar is phenyl optionally substituted with halogen, PA1 n is 0 to 3;
F, Cl, Br, alkyl or alkoxy each of 1 to 4 carbon atoms, cycloalkoxy of 3 to 6 carbon atoms, CF.sub.3, CN, alkylthio of 1 to 4 carbon atoms, SCF.sub.3, OH or alkanoyloxy of 1 to 10 carbon atoms; PA2 alkyl of 1 to 3 carbon atoms, alkoxy of 1 to 3 carbon atoms, haloalkyl of 1 to 3 carbon atoms and 1 to 7 halogen atoms, S(O).sub.t alkyl of 1 to 3 carbon atoms, where t is 1, 2 or 3, dialkylamino of 2 to 6 carbon atoms, halogen, alkylamino of 1 to 3 carbon atoms, CN, NO.sub.2, carboalkoxy of 2 to 6 carbon atoms, COR.sup.9, CONR.sup.12 R.sup.13, SO.sub.2 NR.sup.12 R.sub.13, Ar.sup.2, OAr.sup.2 or SAr.sup.2 ;
Japanese patent 48-40779 (Dainippon) describes the process for preparing compounds of the formula: ##STR1## wherein: R.sup.1 is H, halogen, alkyl, alkoxy or trihalomethyl; and
These compounds are described as being useful as pharmaceuticals since they exhibit psychotropic effects, however, no utility is actually documented.
Nagai et al. (Dainippon) describe psychotropic compounds of the formula: ##STR2## wherein: R.sup.1 is H, Cl or F; and
R.sup.2 is alkyl, alkenyl, benzyl, phenethyl, hydroxyethyl, cyclopropylmethyl or substituted phenylalkyl.
See: Chemical Pharmaceutical Bulletin 25(8) 1911-1922 (1979).
The 3-isomers described in Japanese Patent 48-40779 and in the Chemical Pharmaceutical Bulletin, cited above, do not show the sigma receptor selectivity demonstrated by the compounds of the present invention. It is this sigma receptor selectivity of the compounds of the present invention which makes them so advantageous over the compounds in the prior art. Traditionally, antipsychotic agents have been potent dopamine receptor antagonists. For example, phenothiazines such as chlorpromazine and most butyrophenones such as haloperidol are potent dopamine receptor antagonists. These dopamine receptor antagonists are associated with a high incidence of side effects, particularly Parkinson-like motor effects or extra-pyramidal side-effects (EPS), and dyskinesias including tardive dyskinesias at high doses. Many of these side effects are not reversible even after the dopamine receptor antagonist agent is discontinued.
The present invention is related to antipsychotic agents which are selective sigma receptor antagonists rather than the traditional dopamine receptor blockers known in the art, and therefore the compounds of the present invention have low potential for the typical movement disorder side-effects associated with the dopamine antagonist antipsychotic agents while they maintain the ability to antagonize aggressive behavior and antagonize hallucinogenic-induced behavior.